Interleukin 17 (IL-17)–producing T helper 17 cells (TH-17 cells) have been described as a T helper cell subset distinct from T helper type 1 (TH1) and TH2 cells, with specific functions in antimicrobial defense and autoimmunity. The factors driving human TH-17 differentiation remain controversial. Using a systematic approach combining experimental and computational methods, we show here that transforming growth factor-β, interleukin 23 (IL-23) and proinflammatory cytokines (IL-1β and IL-6) were all essential for human TH-17 differentiation. However, individual TH-17 cell–derived cytokines, such as IL-17, IL-21, IL-22 and IL-6, as well as the global TH-17 cytokine profile, were differentially modulated by TH-17-promoting cytokines. Transforming growth factor-β was critical, and its absence induced a shift from a TH-17 profile to a TH1-like profile. Our results shed new light on the regulation of human TH-17 differentiation and provide a framework for the global analysis of T helper responses.
This is a preview of subscription content
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Mosmann, T.R. & Coffman, R.L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu. Rev. Immunol. 7, 145–173 (1989).
O'Garra, A. Cytokines induce the development of functionally heterogeneous T helper cell subsets. Immunity 8, 275–283 (1998).
Park, H. et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat. Immunol. 6, 1133–1141 (2005).
Harrington, L.E. et al. Interleukin 17–producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat. Immunol. 6, 1123–1132 (2005).
Aujla, S.J., Dubin, P.J. & Kolls, J.K. Th17 cells and mucosal host defense. Semin. Immunol. 19, 377–382 (2007).
LeibundGut-Landmann, S. et al. Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17. Nat. Immunol. 8, 630–638 (2007).
Murphy, C.A. et al. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J. Exp. Med. 198, 1951–1957 (2003).
Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).
Langrish, C.L. et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201, 233–240 (2005).
Mangan, P.R. et al. Transforming growth factor-β induces development of the TH17 lineage. Nature 441, 231–234 (2006).
Veldhoen, M., Hocking, R.J., Atkins, C.J., Locksley, R.M. & Stockinger, B. TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24, 179–189 (2006).
Zhou, L. et al. IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat. Immunol. 8, 967–974 (2007).
Nurieva, R. et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448, 480–483 (2007).
Korn, T. et al. IL-21 initiates an alternative pathway to induce proinflammatory TH17 cells. Nature 448, 484–487 (2007).
Wei, L., Laurence, A., Elias, K.M. & O'Shea, J.J. IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner. J. Biol. Chem. 282, 34605–34610 (2007).
Liang, S.C. et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J. Exp. Med. 203, 2271–2279 (2006).
McGeachy, M.J. et al. TGF-β and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain TH-17 cell–mediated pathology. Nat. Immunol. 8, 1390–1397 (2007).
Acosta-Rodriguez, E.V., Napolitani, G., Lanzavecchia, A. & Sallusto, F. Interleukins 1β and 6 but not transforming growth factor-β are essential for the differentiation of interleukin 17–producing human T helper cells. Nat. Immunol. 8, 942–949 (2007).
Wilson, N.J. et al. Development, cytokine profile and function of human interleukin 17–producing helper T cells. Nat. Immunol. 8, 950–957 (2007).
Chen, Z., Tato, C.M., Muul, L., Laurence, A. & O'Shea, J.J. Distinct regulation of interleukin-17 in human T helper lymphocytes. Arthritis Rheum. 56, 2936–2946 (2007).
Evans, H.G., Suddason, T., Jackson, I., Taams, L.S. & Lord, G.M. Optimal induction of T helper 17 cells in humans requires T cell receptor ligation in the context of Toll-like receptor-activated monocytes. Proc. Natl. Acad. Sci. USA 104, 17034–17039 (2007).
van Beelen, A.J. et al. Stimulation of the intracellular bacterial sensor NOD2 programs dendritic cells to promote interleukin-17 production in human memory T cells. Immunity 27, 660–669 (2007).
Laurence, A. & O'Shea, J.J. TH-17 differentiation: of mice and men. Nat. Immunol. 8, 903–905 (2007).
Weaver, C.T., Hatton, R.D., Mangan, P.R. & Harrington, L.E. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu. Rev. Immunol. 25, 821–852 (2007).
Wang, Y.H. et al. IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC-activated Th2 memory cells. J. Exp. Med. 204, 1837–1847 (2007).
Ivanov, I.I. et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006).
Ivanov, I.I., Zhou, L. & Littman, D.R. Transcriptional regulation of Th17 cell differentiation. Semin. Immunol. 19, 409–417 (2007).
Ringner, M. What is principal component analysis? Nat. Biotechnol. 26, 303–304 (2008).
Zaba, L.C. et al. Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses. J. Exp. Med. 204, 3183–3194 (2007).
Yen, D. et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J. Clin. Invest. 116, 1310–1316 (2006).
Khader, S.A. et al. IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge. Nat. Immunol. 8, 369–377 (2007).
Amadi-Obi, A. et al. TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1. Nat. Med. 13, 711–718 (2007).
Chen, Z. & O'Shea, J.J. Th17 cells: a new fate for differentiating helper T cells. Immunol. Res. published online 3 January 2008 (doi:10.1007/s12026-007-8014-9).
Kastelein, R.A., Hunter, C.A. & Cua, D.J. Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation. Annu. Rev. Immunol. 25, 221–242 (2007).
Veldhoen, M., Hocking, R.J., Flavell, R.A. & Stockinger, B. Signals mediated by transforming growth factor-β initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease. Nat. Immunol. 7, 1151–1156 (2006).
Xie, M.H. et al. Interleukin (IL)-22, a novel human cytokine that signals through the interferon receptor-related proteins CRF2–4 and IL-22R. J. Biol. Chem. 275, 31335–31339 (2000).
Gurney, A.L. IL-22, a Th1 cytokine that targets the pancreas and select other peripheral tissues. Int. Immunopharmacol. 4, 669–677 (2004).
Zenewicz, L.A. et al. Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation. Immunity 27, 647–659 (2007).
Kreymborg, K. et al. IL-22 is expressed by Th17 cells in an IL-23-dependent fashion, but not required for the development of autoimmune encephalomyelitis. J. Immunol. 179, 8098–8104 (2007).
Leonard, W.J. & Spolski, R. Interleukin-21: a modulator of lymphoid proliferation, apoptosis and differentiation. Nat. Rev. Immunol. 5, 688–698 (2005).
Moore, K.W., de Waal Malefyt, R., Coffman, R.L. & O'Garra, A. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 19, 683–765 (2001).
Ito, T. et al. TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand. J. Exp. Med. 202, 1213–1223 (2005).
Trinchieri, G. Interleukin-10 production by effector T cells: Th1 cells show self control. J. Exp. Med. 204, 239–243 (2007).
Jankovic, D. & Trinchieri, G. IL-10 or not IL-10: that is the question. Nat. Immunol. 8, 1281–1283 (2007).
O'Garra, A. & Vieira, P. TH1 cells control themselves by producing interleukin-10. Nat. Rev. Immunol. 7, 425–428 (2007).
Lin, J.T., Martin, S.L., Xia, L. & Gorham, J.D. TGF-β1 uses distinct mechanisms to inhibit IFN-γ expression in CD4+ T cells at priming and at recall: differential involvement of Stat4 and T-bet. J. Immunol. 174, 5950–5958 (2005).
Gorelik, L., Constant, S. & Flavell, R.A. Mechanism of transforming growth factor β-induced inhibition of T helper type 1 differentiation. J. Exp. Med. 195, 1499–1505 (2002).
Manel, N., Unutmaz, D. & Littman, D.R. Human TH-17 differentiation requires transforming growth factor-β and induction of the nuclear receptor RORγt. Nat. Immunol. (in the press).
We thank O. Lantz, S. Denépoux, F. Barrat, C. Théry, P. Benaroch, I. Fernandez, Z. Maciorowsky and H. Kitamura for suggestions and critical reading of the manuscript; and Z. Maciorowsky, C. Guérin and A. Viguier for cell sorting. Yssel's medium was a gift from H. Yssel (Institut National de la Santé et de la Recherche Médicale). Supported by the European Community Sixth Framework Programme (Marie Curie Excellence Grant 014162).
About this article
Cite this article
Volpe, E., Servant, N., Zollinger, R. et al. A critical function for transforming growth factor-β, interleukin 23 and proinflammatory cytokines in driving and modulating human TH-17 responses. Nat Immunol 9, 650–657 (2008). https://doi.org/10.1038/ni.1613
Cancer Cell International (2022)
Journal of Neuroinflammation (2022)
A multivariate modeling framework to quantify immune checkpoint context-dependent stimulation on T cells
Cell Discovery (2022)
Immune Inhibitory Properties and Therapeutic Prospects of Transforming Growth Factor-Beta and Interleukin 10 in Autoimmune Hepatitis
Digestive Diseases and Sciences (2022)
Advances in Traditional Medicine (2022)